Delivery devices for administering a beneficial agent to a biological fluid environment of use are known in the prior art. Representative examples of various types of delivery devices are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,995,632; 4,111,202; 4,111,203; 4,203,439; 4,327,725; and 4,612,008; all of which are incorporated herein by reference. The delivery devices described in the above patents operate successfully for their intended use and they can deliver many beneficial agents for their intended effects. However, it has been observed that their use can be limited because they lack the necessary elements to deliver beneficial agents that are sensitive to fluids and to fluids containing biological gases. Their use may be limited because beneficial agents that are sensitive to such aqueous biological fluids or to other fluids external to the delivery device may be adversely affected by fluids that enter the device and contact the beneficial agents during operation of the device. Examples of such fluid-sensitive agents include proteins, peptides, and hormones. Moreover, the prior art devices lack the necessary means for their use as implant devices for dispensing such sensitive agents to a biological fluid-rich environment of use.
To overcome the limitations associated with the prior art delivery devices, a delivery device was developed and is described and claimed in U.S. Pat. No. 5,034,229. This delivery device comprises a compartment, one portion of which is impermeable to fluid and contains a fluid-sensitive drug protected from a fluid environment and a second portion of which is permeable to fluid and contains an expandable driving member for administering the drug to the fluid environment of use. The system has been found to be particularly useful as an implant in livestock for delivering a fluid-sensitive drug over a broad range of dosage delivery rates according to a predetermined time-release pattern.
Although in vitro tests and in vivo tests on isolated animals indicated satisfactory system performance, in vivo tests under field conditions of the delivery device of U.S. Pat. No. 5,034,229 in livestock demonstrated an undesirably high failure rate, either by failing to deliver the beneficial drug at the desired rates or by failing to deliver the required dosage of the drug or by the fluid-sensitive drug in the device coming into contact with fluid prematurely and becoming adversely affected prior to its delivery into the fluid environment of the host animal. The discrepancy between in vivo tests on isolated animals and on animals under field conditions was totally unexpected, not readily explained, and could adversely affect the commercialization of the delivery device.
It was discovered that the failure of the devices of U.S. Pat. No. 5,034,229 under field conditions was attributable to damage to the portion of the compartment containing the expandable driving member or damage to the junction between the permeable and impermeable portions of the compartment as a result of radially applied transient mechanical forces, which forces are the result of such actions as the implant procedure itself; behavior patterns of the host animals, such as animal-to-animal interaction which is often violent, and collisions of the animals into guardrails of pens or other structures; and miscellaneous in vivo forces which act upon the implanted delivery device. It was also discovered that the frequency of failure could be greatly reduced if these delivery devices were rendered more robust and resistant to such transient mechanical forces in a manner that does not interfere with delivery of the protected beneficial agent at a controlled rate.
Accordingly, an improvement to the delivery device was developed and is described and claimed in PCT patent publication WO 92/00728 to Magruder et al. for Delivery Device with a Protective Sleeve. This delivery device is similar to that of U.S. Pat. No. 5,034,229 except that it additionally has a protective sleeve means extending from the first wall section of the housing to cover and protect the second wall section of the housing and the junction of the first and second sections.
While the addition of a protective sleeve has provided substantial protection to the device, resulting in reduced failures of the system and increased effectiveness, at the same time it has added extra weight and bulk to the system, which is undesirable in many types of use, such as an implant device. Also, an additional part or piece, the sleeve, is now required and an additional step in the manufacture of the device is now necessary, both of which add to the cost of the device.
Therefore, it is still desirable to provide an implantable delivery device that is of a smaller size and lighter weight while also being robust and resistant to mechanical forces in vivo.
Another disadvantage recently discovered with the devices of both U.S. Pat. No. 5,034,229 and WO 92/00728 is that certain stable and resorbable somatotropin formulations to be delivered are osmotically active, having the same osmotic activity as a saturated solution of sodium chloride. At the same time, the osmotic permeability to water of the substantially impermeable reservoir wall surrounding the formulation is in fact finite. The combination of these two characteristics results in absorption of some water through the reservoir wall and dilution and some inactivation of somatotropin inside the reservoir. In vitro and in vivo testing results from prior art devices have demonstrated up to 20-25% dilution of the fluid-sensitive beneficial agent formulation at 4-5 weeks of delivery.
Accordingly, it is desirable to provide a delivery device that is not only robust and resistant to mechanical forces in vivo but provides improved stability for the benficial agent formulation in vivo; that is, it does not cause the dilution and inactivation of an active agent to be delivered by the device.